Mechanism of Prolongation of the R-R Interval
with Electrical Stimulation
of the Carotid Sinus Nerves in Man
By Dwain L. Eckberg, Gerald F. Fletcher, and Eugene Braunwald
ABSTRACT
To elucidate the mechanism by which stimulation of the carotid sinus nerves
prolongs the R-R interval, the effects of activating an implanted carotid sinus
nerve stimulator were studied in eight patients at varying levels of background
autonomic activity and with varying types of efferent autonomic blockade.
Beta-receptor blockade was induced with intravenous propranolol, 0.20 mg/kg,
and parasympathetic blockade with intravenous atropine, 0.04 mg/kg. In the
supine position, average prolongation of the R-R interval due to stimulation of
the carotid sinus nerves was 269 ± 56 msec prior to autonomic blocking drugs,
442 ± 214 msec after propranolol (NS), and 44 ± 13 msec after propranolol
and atropine (P < 0.025). Comparable changes were produced in the standing
position. With moderate treadmill exercise, stimulation of the carotid sinus
nerves prolonged the R-R interval by only 40 ± 30 msec prior to blocking
drugs, 62 ± 19 msec after propranolol, and 40 ± 30 msec after propranolol and
atropine. It is concluded that the prolongation of the R-R interval produced by
stimulation of the carotid sinus nerves is secondary to augmented
parasympathetic activity, and the attenuation of this response during erect
exercise appears to be due to a centrally mediated reduction in the
responsiveness of the parasympathetic nervous system to baroreceptor
stimuli.
KEY WORDS
baroreceptor
carotid sinus reflex
beta-receptor blockade
• The baroreceptor reflex is of fundamental
importance to circulatory control. Although it
is generally agreed that baroreceptor-induced
vasodilatation results from central withdrawal
of adrenergic tone (1, 2), considerable
controversy exists about the mechanism of
baroreceptor-induced slowing of heart rate. It
has been proposed that, like reflex vasodilatation, reflex reduction of sinoatrial automaticity
is mediated primarily by withdrawal of
adrenergic tone (3). Most investigators believe that this reduction of automaticity is
From the Department of Medicine, University of
California, School of Medicine, San Diego, California
92103.
This work was supported by Program Project Grant
HE 12373 from the National Heart and Lung
Institute, a Grant from the San Diego County Heart
Association, and a Special Research Fellowship HE
39537.
Received July 21, 1971. Accepted for publication
October 20, 1971.
Circulation Research, Vol. XXX, January 1972
parasympathetic blockade
autonomic nervous system
secondary to reciprocal withdrawal of adrenergic stimulation and augmentation of parasympathetic restraint (4-6). Other studies,
however, in experimental animals and man
suggest that it results primarily from increased
parasympathetic activity (7-12).
The baroreceptor reflex has been studied
extensively in anesthetized dogs by measuring
the effects of increasing afferent nerve trafficin the carotid sinus nerves (4,13-15). We have
had the unique opportunity to study baroreceptor function in unsedated man, using direct
electrical stimulation of the carotid sinus
nerves, and have utilized this opportunity to
clarify the mechanism of baroreceptorinduced prolongation of the R-R interval.
Selective blockade of the adrenergic and
parasympathetic systems was accomplished
pharmacologically, and observations were carried out at three levels of background
autonomic activity.
131
132
Methods
Eight patients averaging 62 years of age
(range 43 to 77 years) were studied without
sedation in the postabsorptive state. Bilateral
carotid sinus nerve stimulator electrodes had been
implanted in a manner described previously (16)
for treatment of uncontrollable recurrent supraventricular tachycardia in two patients (17),
incapacitating angina pectoris in five patients
(18, 19), and angina associated with recurrent
paroxysmal atrial tachycardia in one patient.
Three patients had undergone selective coronary
arteriography and were found to have occlusion
of the right coronary artery and extensive disease
of the major branches of the left coronary artery.
All patients were free of signs and symptoms of
congestive heart failure at the time of study. One
patient had systolic hypertension; all other
patients had normal resting systolic and diastolic
arterial pressures.
All patients were in sinus rhythm throughout
the study. Carotid sinus nerve stimulation
(CSNS) did not alter the P-R intervals significantly, and therefore R-R intervals were used to
express sinoatrial automaticity. Changes in the RR interval were studied in preference to changes
in heart rate, because the R-R interval is a
directly measured function that responds linearly
to changes in baroreceptor activity, whereas heart
rate is derived mathematically and is a reciprocal
function that responds hyperbolically.
The intensity of the electrical stimulus and the
frequency of stimulation were adjusted individually to provide optimum therapeutic effects and
were held constant during each series of
experiments on each patient. Impulses of 0.3msec duration were delivered at an average
frequency of 81 cps (range 40 to 125) at 4.1 ± 1
(SE) v with an external radiofrequency stimulator
(Angistat, Medtronic, Inc.).
Brachial arterial pressure, obtained through an
indwelling Cournand needle connected to a
Statham P23AA strain gauge, and a modified V-l
electrocardiographic lead were recorded on a
multichannel recorder. The effects of CSNS were
studied when the patients were supine and when
they were standing and during horizontal treadmill exercise at 1.7 mph. CSNS was begun after
90 seconds of treadmill exercise. Stimulation was
continued for 2 minutes in most instances but was
terminated earlier if symptoms due to bradycardia
or hypotension appeared. Measurements of R-R
intervals and systolic, diastolic, and mean arterial
pressures were made immediately prior to the
onset of stimulation and, commencing 15 seconds
after the onset of stimulation, at 15-second
intervals for 2 minutes or until the cessation of
CSNS. Thus, measurements of hemodynamic
changes were not made until at least 15 seconds
ECKBERG, FLETCHER, BRAUNWALD
of CSNS had elapsed. The maximum changes
produced by CSNS are reported. Statistical
analyses were performed with Student's paired ttest to compare the average responses to CSNS
under different conditions. Differences were
considered to be statistically significant when
P < 0.05.
The role of the adrenergic system in inducing
reflex changes in the R-R interval was elucidated
in six patients by comparing the response of the
R-R interval to CSNS before and within 15
minutes after the intravenous administration of
propranolol, 0.20 mg/kg. Jose and Taylor (20)
have shown that following this dose of propranolol given to supine subjects additional propranolol produces no further slowing of the heart
rate, and studies from our own laboratory (21)
have shown that propranolol, 0.15 mg/kg,
reduces the effectiveness of infused isoproterenol
by at least 90%.
The role of the parasympathetic system was
determined by examining the effects of the
intravenous administration of atropine sulfate,
0.04 mg/kg, on the response to CSNS in four of
the patients who had received propranolol. In
addition, the effects of isolated parasympathetic
blockade on the response to CSNS were determined in the other four patients. Jose and Taylor
(20) and Chamberlain and co-workers (22) have
shown that atropine doses in excess of 0.04
mg/kg produce no further acceleration of the
heart rate, suggesting that the parasympathetic
blockade produced by this dose is complete.
Atropine was given within 20 minutes after the
administration of propranolol, and all studies
were completed within 20 minutes after the
administration of atropine.
Results
HEMODYNAMIC RESPONSES TO CSNS
A typical hemodynamic response to CSNS
in the control condition is depicted in Figure
1. The R-R interval rose abruptly with the
onset of stimulation and then gradually
returned toward control levels as electrical
stimulation was continued. Systolic and diastolic arterial pressures also fell rapidly with
the onset of stimulation, gradually drifted lower as stimulation was continued, and returned
rapidly toward normal with the cessation of
stimulation. Maximum prolongation of the RR interval occurred within the first 30 seconds
in most instances (73%), whereas maximum
fall in mean arterial pressure occurred during
the first 30 seconds in a minority of studies
Circulation Research, Vol. XXX, January 1972
133
MECHANISM OF HEART RATE SLOWING
36 ± 5 mm Hg during CSNS in the supine
position. This decline was not altered significantly by the erect position, exercise, or
adrenergic or parasympathetic blockade (Table 1). Changes in systolic and diastolic
pressure paralleled those observed in mean
arterial pressure.
RESPONSES OF THE R-R INTERVAL TO PHYSIOLOGICAL
AND PHARMACOLOGICAL INTERVENTIONS
100
120
140
Time, seconds
FIGURE 1
Typical R-R interval and arterial pressure responses
to bilateral carotid sinus nerve stimulation (CSNS).
The arrows indicate the onset and duration of CSNS.
AP = arterial pressure; R-R = R-R interval.
(46%). Neither beta-receptor nor parasympathetic blockade altered the time sequence of
the heart rate and arterial pressure responses
to carotid sinus nerve stimulation.
MEAN ARTERIAL PRESSURE CHANGES
IN RESPONSE TO CSNS
The mean arterial pressure declined by
The average R-R interval in the supine
position prior to stimulation was 782 ± 22
msec, and after propranolol it rose to 975 ± 21
msec. With the assumption of the erect
posture, the average R-R interval in the
absence of pharmacological blockade fell to
727 ± 38 msec and rose to 971 ± 29 msec
following propranolol. The average R-R interval fell to 598 ± 32 during treadmill exercise
(P<0.05) and rose to 791 ± 15 msec
(P < 0.01) with propranolol. R-R intervals in
the patients receiving only atropine averaged
667 ±52 in the supine position, 619 ± 31
standing, and 593 msec during treadmill
exercise.
CHANGES IN THE R-R INTERVAL
IN RESPONSE TO CSNS
Changes in the R-R interval with CSNS in
the supine position are depicted in Figure 2.
TABLE 1
Effects of Carotid Sinus Nerve Stimulation
C
Control
Supine
Standing
Walking
Propranolol
Supine
Standing
Walking
Propranolol
and atropine
Supine
Standing
Walking
Atropine
Supine
Standing
Walking
R-R interval (msec)
S
A
Mean arterial pressure (mm Hg)
A
C
S
782 =t= 22
727 ± 38
598 ± 32
1051 ± 53
965 ± 56
682 ± 40
269 ± 56
238 ± 60
85 ± 13
92 ± 8
90 ± 4
103 ± 6
56 ± 7
53 ± 23
75 * 9
36 =*= 5
37 ± 5
21 =*= 4
975 ± 21
971 ± 29
791 ± 15
1417 ± 198
1217 ± 66
853 * 28
442 ± 214
246 ± 55
62 ± 19
84 ± 6
81 =t 6
87 * 8
51 ± 2
53 =*= 8
69 =*= 10
33 =•= 4
28 ± 3
18 =*= 6
888 ± 45
854 =t 32
807 ± 23
931 ± 42
927 ± 38
846 ± 23
44 ± 13
73 ± 40
40 ± 13
87 ± 3
69 =<= 5
72 ± 7
63 ± 10
40 ± 2
51 ± 3
36 ± 5
30 ± 8
21 ± 4
667 ± 52
619 ± 31
749 ± 85
697 ± 42
82 ± 36
78 ± 25
593
642
49
58
57
97
18
34
24
76
91
120
C = control, prior to stimulation; S = observations during stimulation; values are means ± SE.
Circulation Research, Vol. XXX,
January 1972
134
ECKBERG, FLETCHER, BRAUNWALD
Control
Propronolol
»Atropine alone
• Atropine ond Propronolol
1400-
-5* 1000>
£ 800c
CC 6 0 0 400H
FIGURE 2
Effects of carotid sinus nerve stimulation on the R-R
interval in the supine position. The first point for
each subject is the average control R-R interval prior
to CSNS, and the second point represents the maximum change during CSNS. Mean values are indicated
by arrows.
The average prolongation of the R-R interval
was 269 ± 56 msec in the control state. Betareceptor blockade did not diminish this
response; in fact, after propranolol, the
average prolongation of the R-R interval was
increased to 442 ± 214 msec. However, this
was not a significant change. One patient
experienced an inordinate amount of prolongation of the R-R interval with CSNS after
propranolol (1412 msec) and was primarily
responsible for the increased average for the
entire group. The average change for the
other five patients was 230 msec prior to
propranolol and was almost identical, 228
msec, after propranolol. Thus, in the supine
position, there was no evidence that withdrawal of adrenergic stimulation of the sinoatrial node contributed to the prolongation
of the R-R interval during CSNS.
In contrast, CSNS resulted in significantly
less prolongation of the R-R interval in all patients after administration of atropine with
or without prior treatment with propranolol,
the R-R interval increased by an average of only 44 ± 13 msec in the four patients
who received atropine after propranolol and
by 82 ± 36 msec in the other four patients
who received atropine without prior treatment with propranolol.
The effects of CSNS on patients in the
standing position were similar to those observed in the supine position (Fig. 3).
Prolongation of the R-R interval in the control
state averaged 238 ± 60 msec and was almost
identical after propranolol, averaging 246 ±
55 msec. Similarly, atropine reduced the prolongation of the R-R interval produced by
CSNS; when atropine was given following
propranolol, CSNS produced a prolongation
of the R-R interval which averaged only
73 ± 40 msec, and when atropine was given
without prior treatment with propranolol, it
averaged 78 ± 25 msec.
During treadmill exercise, the responses to
CSNS were significantly reduced, regardless
of the presence or absence of autonomic
blocking drugs (Fig. 4). Lengthening of the
R-R interval averaged only 85 ± 13 msec prior
to drug administration, 62 ± 19 msec after
propranolol, 40 ± 15 msec after atropine and
propranolol, and 49 msec after atropine alone.
Changes in the R-R interval with CSNS
during physiological and pharmacological interventions are summarized in Figure 5.
Discussion
In this investigation, the mechanism of the
baroreceptor-induced lengthening of the R-R
interval was studied using direct electrical
stimulation of the carotid sinus nerves in
unsedated patients. Since the mechanism of
prolongation of the R-R interval might be a
function of background autonomic activity,
the latter was varied physiologically by
Control
Propranolol
• Atropine alone
• Atropine and Propronolol
1400 o
8)1200-1
E
•5 1000« 800-
600400-1
FIGURE 3
Effects of CSNS on the R-R interval for each patient
in the standing position. See Figure 2 for explanation.
Circulation Research, Vol. XXX, January 1972
135
MECHANISM OF HEART RATE SLOWING
Propranolo!
Control
0
• Atropina alon*
• Atroptnt and Propronolol
1400 -
<u
in
£ 12001
1000-
"c
800600400FIGURE 4
Effects of CSNS on the R-R interval during light
treadmill exercise. See Figure 2 for explanation.
changing posture and by treadmill exercise.
To study the relative importance of the two
components of the autonomic nervous system,
comparisons of the effects of CSNS before and
after selective blockade of the adrenergic and
parasympathetic systems were carried out.
The effects of sympathetic withdrawal on
sinoatrial automaticity are known to appear
later than the effects of parasympathetic
augmentation (23). For this reason, no
hemodynamic measurements were made until
at least 15 seconds of CSNS had elapsed;
changes observed at this time and later during
CSNS should have included both sympathetic
and parasympathetic components.
When base-line sympathetic activity was
lowest, as in the supine resting subjects,
prolongation of the R-R interval induced by
CSNS was not reduced by beta-receptor
blockade, even though propranolol itself
significantly prolonged the average R-R interval (782 to 975 msec). If the slowing of heart
rate during CSNS was due to a significant
extent to withdrawal of adrenergic stimulation, then propranolol would have reduced the
degree of prolongation of the R-R interval.
Thus, under the conditions of this study,
withdrawal of adrenergic stimulation of the
sinoatrial node does not appear to play a
significant role in the observed prolongation of
the R-R interval by CSNS. In the unblocked
state, a moderate reduction in R-R interval
was produced by standing; this reduction was
Circulation Research, Vol. XXX,
January 1972
prevented by propranolol, which increased the
standing R-R interval from 727 to 971 msec,
and therefore this postural reduction in R-R
interval may be presumed to have resulted
from augmented adrenergic nervous activity,
as had been suggested by our previous studies
(24). Despite this higher level of adrenergic
drive, propranolol did not alter the prolongation of the R-R interval produced by CSNS. It
appears, therefore, that even in the presence
of the heightened adrenergic activity produced by the erect position, prolongation of
the R-R interval induced by CSNS does not
result to any large extent from adrenergic
withdrawal. During light treadmill exercise, a
further reduction in R-R interval was
observed, and the increase in R-R interval
after propranolol (from 598 to 791 msec)
suggested that most of the shortening of the
R-R interval during exercise was secondary in
Control
Propranolol
Propranolol
. + .
Atropine
FIGURE 5
Average lengthening of the R-R interval for all subjects. Means ± 1 SE are shown. The numbers of patients studied are indicated in black circles.
136
part to increased adrenergic nervous activity.
During exercise, even prior to autonomic
blockade, CSNS produced relatively little
prolongation of the R-R interval, and propranolol did not modify this response.
These experiments indicate that although
the adrenergic nervous system plays a definite
role in altering heart rate to levels appropriate
to position and activity, it does not appear to
be of great importance in changes in R-R interval produced reflexly by activation of the carotid sinus nerves. This conclusion is strengthened by other observations in this (8) and
other laboratories (12) in normal subjects
whose carotid sinus and aortic arch receptors
were activated by increasing the systemic
arterial pressure. Instead, the prolongation of
the R-R interval resulting from CSNS appears
to be due almost entirely to increased
parasympathetic restraint. Thus, in contrast to
the effects of propranolol, atropine markedly
reduced the average lengthening of the R-R
interval resulting from CSNS, both in the
supine and standing positions. This effect was
observed regardless of whether the subject
was pretreated with propranolol. Although
atropine significantly reduced the average R-R
interval in the supine and standing positions,
it did not appreciably alter it during treadmill
exercise. Thus, it appeared that exercise
resulted in physiological withdrawal of parasympathetic tone or reduction in responsiveness of sinoatrial pacemaker cells. In this
context, the failure of CSNS to significantly
prolong the R-R interval during treadmill
exercise prior to the administration of any
autonomic blocking agents suggests that the
withdrawal of parasympathetic tone is associated with a centrally mediated elevation of
threshold or reduction in gain of the carotid
sinus reflex or both.
During CSNS, the withdrawal of adrenergically induced vasoconstriction results in hypotension which is perceived by aortic arch
baroreceptors which reflexly counteract the
hemodynamic effects of CSNS. In this context,
the return of the R-R interval toward control
levels while arterial pressure remained depressed during continued CSNS suggests that
ECKBERG, FLETCHER, BRAUNWALD
the baroreceptors in the aortic arch are more
important in controlling sinoatrial automaticity than those in the carotid sinuses, and the
failure of arterial pressure to rise during
continued stimulation (Fig. 1) suggests the
primacy of the carotid baroreceptors in the
physiological regulation of peripheral resistance; this inference is consistent with observations made in conscious dogs (9).
Direct electrical CSNS simulates the physiological response to mechanical distention of
the carotid sinuses resulting from rising
arterial pressure; the present study, therefore,
does not shed light on the effects of lowering
arterial pressure, and it is entirely possible
that the adrenergic system plays a more
important role in the shortening of the R-R
interval resulting from hypotension. This
suggestion is supported by earlier findings in
our laboratory; cardioacceleration in dogs
resulting from nitroglycerin-induced hypotension can be attenuated by propranolol (7), as
can that produced in humans by upright
tilting (18).
The findings in the present investigation are
consistent with the findings of Scher and
Young (10) and Vatner and co-workers (9)
who studied the response to electrical CSNS
in experimental animals. However, our conclusions are at variance with those of
Devleeschhouwer and Heymans (4) who
measured the slowing of heart rate which
occurs after release of bilateral common
carotid artery occlusive cuffs in dogs and
found that this response was significantly
reduced by drugs that block beta-receptors
but not by atropine. Similarly, Berkowitz and
co-workers demonstrated in dogs that slowing
of heart rate produced by CSNS can be
blocked largely by propranolol but not by
atropine (3). Both of these latter studies were
carried out under general anesthesia after
extensive surgical procedures, and the disparity between these results and those of the
present study may have resulted from changes
in autonomic cardiovascular regulation produced by anesthetic agents (25-28). In addition to interfering with the normal parasympathetic responses to baroreceptor stimulation,
Circulation Research, Vol. XXX, January 1972
137
MECHANISM OF HEART RATE SLOWING
general anesthesia may also alter the pattern
of adrenergic responses to CSNS. Thus,
Vatner and co-workers found that CSNS
produced more cardiac slowing after atropine
in anesthetized animals than it did in
conscious animals (26).
In addition to providing increased understanding of the physiological control of heart
rate and arterial pressure, this study carries
implications regarding the therapeutic uses of
electrical CSNS. The failure of propranolol to
modify the hemodynamic effects of CSNS
suggests that treatment with this drug does
not contraindicate the use of therapeutic
electrical CSNS in the treatment of angina
pectoris. Indeed, the two modalities could be
considered complementary in reducing myocardial oxygen requirements, CSNS by reducing arterial pressure and propranolol by
slowing heart rate. On the other hand, our
data suggest that anticholinergic therapy may
compromise the effectiveness of therapeutic
CSNS.
The present findings also shed light on the
mechanism of interruption of paroxysms of
supraventricular tachycardia by means of
electrical CSNS. This mode of therapy
abolished almost all episodes in the three
patients in this investigation who suffered
from this disorder. The increase in vagal
activity demonstrated in this study to result
from CSNS would not be expected to
terminate the tachycardia if the latter were
due to rapid impulse formation in an ectopic
focus (29). However, it has been proposed
that paroxysmal atrial tachycardia is related to
reentrant activity resulting from reciprocation
of an impulse between the atrium and the AV
node (30), and the efficacy of CSNS in
terminating episodes may be related to the
parasympathetically mediated extinction of a
stimulus in the atrionodal tissue.
In conclusion, the results of this study on
the effects of direct electrical stimulation of
the carotid sinus nerves indicate that: (1)
Although augmented beta-receptor stimulation of the sinoatrial node reduces the R-R
interval, withdrawal of this stimulation does
not appear to play a significant role in the
Circulation Research, Vol. XXX, January 1972
prolongation of the R-R interval produced by
CSNS. (2) Prolongation of the R-R interval
with CSNS is nearly abolished by atropine,
and it is therefore believed to result from
increased parasympathetic nervous activity.
(3) Light treadmill exercise, which is associated with augmented sympathetic drive and
withdrawal of parasympathetic restraint, produces a centrally mediated reduction in the
responsiveness of the parasympathetic nervous
system to CSNS. (4) CSNS-induced reductions in arterial pressure do not appear to be
influenced in a major way by posture, activity,
or by beta-receptor or parasympathetic blockade.
Acknowledgment
The cooperation of Dr. Nina S. Braunwald, who
implanted the carotid sinus nerve stimulators, and of
Mr. D. Haas, who assisted in the studies, is gratefully
acknowledged.
References
1. BRONK, D.W., FERGUSON, L.K., MARGARIA, R.,
AND SOLANDT, D.Y.: Activity of the cardiac
sympathetic centers. Am J Physiol 117:237249, 1936.
2.
BRONK, D.W., PITTS, R.F., AND LABRABEE, M.G.:
Role of hypothalamus in cardiovascular regulation. Res Publ Assoc Res Nerv Ment Dis
20:323-341, 1939.
3. BERKOWITZ, W.D., SCHERLAG, B.J., STEIN, E., AND
DAMATO, A.N.: Relative roles of sympathetic
and parasympathetic nervous systems in the
carotid sinus reflex in dogs. Circ Res
24:447-455, 1969.
4.
DEVLEESCHHOUWEH,
G.R.,
AND HEYMANS,
C:
Baroreceptors and reflex regulation of heart
rate. In Baroreceptors and Hypertension, edited
by P. Kezdi. New York, Pergamon Press, 1967,
pp 187-190.
5.
GELLHORN, E.: Significance of the state of the
central autonomic nervous system for quantitative and qualitative aspects of some cardiovascular reactions. Am Heart J 67:106-120,
1964.
6. THAMES, M.D., AND KONTOS, H.A.: Mechanisms
of baroreceptor-induced changes in heart rate.
Am J Physiol 218:251-256, 1970.
7. GLICK, G., AND BRAUNWALD, E.: Relative roles of
the sympathetic and parasympathetic nervous
systems in the reflex control of heart rate. Circ
Res 16:363-375, 1965.
8. ECKBERC, D.L., DRABINSKY, M., AND BRAUNWALD,
E.:
Defective
parasympathetic
control in
138
ECKBERG, FLETCHER, BRAUNWALD
patients with heart disease. N Engl J Med
285:877-883, 1971.
LER, A.S., STAMPFER, M., COHEN, L.S., REIS,
R.L., BRAUNWALD, N.S., AND BRAUNWALD, E.:
Treatment of angina pectoris by electrical
stimulation of the carotid sinus nerves. N Engl
J Med 280:971-978, 1969.
9. VATNEH, S.F., FRANKLIN, D., VAN CITTERS, R.L.,
AND BRAUNWALD, E.: Effects of carotid sinus
nerve stimulation on blood flow distribution in
conscious dogs at rest and during exercise. Circ
Res 27:495-503, 1970.
20.
11.
NATHANSON,
M.H., AND MILLER,
H.:
21. EPSTEIN,
LEON, D.F., SHAVER, J.A., AND LEONARD, J.L.:
Reflex heart rate control in man. Am Heart J
80:729-739, 1970.
13. MOISSEJEFF, E.: Zur Kenntnis des Carotissinusreflexes. Z Gesamte Exp Med 53:696-704,
1927.
14. HEYMANS, C : Perfusion, chez un chien B, du
sinus carotidien isole et anastomose sur la
circulation carotido-jugulaire d'un chien A. C
R Soc Biol (Paris) 100:196-201, 1929.
15.
HEYMANS, C , AND BOUCKAERT, J.J.:
16.
22.
BRAUNWALD, E., EPSTEIN, S.E., GLICK, G.,
WECHSLER, A.S., AND BRAUNWALD, N.S.: Relief
23.
BRAUNWALD, E., SOBEL, B.E., AND BRAUNWALD,
N.S.: Treatment of paroxysmal supraventricular tachycardia by electrical stimulation of the
carotid-sinus nerves. N Engl J Med 281:885888, 1969.
18.
EPSTEIN, S.E., BEISER, G.D., GOLDSTEIN, R.E.,
STAMPFER, M., WECHSLER, A.S., GLICK, G.,
AND BRAUNWALD, E.: Circulatory effects of
electrical stimulation of the carotid sinus nerves
in man. Circulation 40:269-176, 1969.
19.
EPSTEIN, S.E., BEISER, G.D., GOLDSTEIN, R.E.,
REDWOOD, D., ROSING, D.R., GLICK, G., WECHS-
Autonomic
S.E., ROBINSON, B.F., KAHLER,
R.L.,
CHAMBERLAIN, D.C., TURNER, P., AND SNEDDON,
WARNER, H.H., AND RUSSELL, R.O., JH.: Effect of
combined sympathetic and vagal stimulation
on heart rate in the dog. Circ Res 24:567-573,
1969.
24.
ROBINSON,
B.F., EPSTEIN,
S.E., BEISER,
G.D.,
AND BRAUNWALD, E.: Control of heart rate by
the autonomic nervous system. Circ Res
19:400-411, 1966.
25.
BRISTOW, J.D., PRYS-ROBERTS, C , FISHER, A.,
PICKERING, T.G., AND SLEIGHT, P.: Effects of
anesthesia on baroreflex control of heart rate in
man. Anesthesiology 31:422-428, 1969.
26.
VATNER, S.F., FRANKLIN, D., AND BRAUNWALD,
E.: Effects of anesthesia and sleep on the
circulatory response to carotid sinus nerve
stimulation. Am J Physiol 220:1249-1255,
1971.
of angina pectoris by electrical stimulation of
the carotid-sinus nerves. N Engl J Med 277:
1278-1283, 1967.
17.
R.R.:
J.M.: Effects of atropine on heart-rate in
healthy man. Lancet 2:11-15, 1967.
Le sinus
carotidien, zone reflexegene regulatrice du
tonus des vaisseaux cephaliques. C R Soc Biol
(Paris) 100:202-204, 1929.
AND TAYLOR,
AND BRAUNWALD, E.: Effects of beta-adrenergic blockade on the cardiac response to
maximal and submaximal exercise in man. J
Clin Invest 44:1745-1753, 1965.
Clinical
observations on a new epinephrine-like compound, methoxamine. Am J Med Sci
223:270-279, 1952.
12.
A.D.,
blockade by propranolol and atropine to study
intrinsic myocardial function in man. J Clin
Invest 48:2019-2031, 1989.
10. SCHER, A.M., AND YOUNG, A.C.: Reflex control
of heart rate in the unanesthetized dog. Am J
Physiol 218:780-789, 1970.
JOSE,
27. HEYMANS, C , AND NEIL, E.: Reflexogenic Areas
of the Cardiovascular System. Boston, Little,
Brown & Co., 1958, pp 101-106.
28.
NEIL, E., REDWOOD, C.R.M., AND SCHWEITZER,
A.: Pressor responses to electrical stimulation
of carotid sinus nerves in cats. J Physiol
(Lond) 109:259-271, 1949.
29. HAN, J.: Mechanism of paroxysmal atrial
tachycardia. Am J Cardiol 26:329-330, 1970.
30.
BICGER, J.T., AND GOLDREYER, B.N.: Mechanism
of supraventricular
42:673-688, 1970.
tachycardia.
Circulation
Circulation Research, Vol. XXX, January 1972